This R01 application describes an Alzheimer's disease (AD) drug discovery program that is based on the discovery that a lipid oxidation product within the AD brain activates a defined neuronal receptor, with a resulting increase of amyloid beta (Ab) peptide production and accumulation. More specifically, the oxidized arachidonic acid product, isoprostane 2FaIII, binds to the thromboxane A2 (TP) receptor on neurons and causes an increase in expression of the amyloid precursor protein (APP) from which Ab is derived. Accordingly, a TP receptor blocker would be expected to prevent isoprostane-mediated elevation of APP and Ab, and this has been confirmed by showing that an antagonist to this receptor significantly reduces Ab levels and plaque deposition in the established Tg2576 mouse model of AD. Although these results provide important validation of a new therapeutic strategy of using TP receptor blockers for the treatment of AD, we have discovered that existing antagonists to this target have poor blood-brain barrier penetration that limits their usefulness as potential AD therapeutics. Accordingly, we propose in this application to develop novel, brain- penetrant TP receptor blockers for the treatment of AD, with the specific aims of: 1) synthesizing new, improved TP receptor antagonists and evaluating them in a focused set of in vitro potency and safety assays, followed by mouse pharmacokinetic testing, to identify brain-penetrant compounds;2) conducting scale-up synthesis and subsequent testing of the 2-5 best candidate compounds from Aim 1 in normal mice to determine their toxicological profiles and relative therapeutic indices;and 3) evaluating the 1-3 compounds with the best safety profiles and therapeutic indices in the Tg2576 transgenic mouse model of AD. The successful completion of these studies will result in one or more novel drug candidates from a new class of AD therapeutics that will have the potential of decreasing Ab peptides and senile plaques in the AD brain. PUBLIC HEALTH RELEVANCE: The studies proposed within this R01 application are directed toward the development of a new class of drugs for the treatment of Alzheimer's disease (AD). If successful, such drugs might have the ability to slow AD progression and/or improve the cognitive performance of those with this disease.